Medicinal aerosol formulations

ABSTRACT

The use of solid, pharmaceutically acceptable salts of cromoglycic acid and/or nedocromil as carriers in a therapeutically and prophylactically inefficacious amount in suspension aerosol formulations of pharmaceutical active compounds improves the dispersion properties, increases the chemical and physical stability of moisture-sensitive active compounds, makes possible a more accurate dosage, in particular even of low-dose active compounds, and as a rule permits the abandonment of surface-active agents.

FIELD OF THE INVENTION

The present invention relates to medicinal suspension aerosolformulations and to a novel use of cromoglycic acid and nedocromilsalts.

BACKGROUND OF THE INVENTION

For the preparation of medicinal metered-dose aerosols, as a rulesuitable propellants are only those which can be liquefied at roomtemperature and which lead on successive spraying of the contents to noor only in any case to a slight decrease in the internal pressure in thecontainer. In the past, customarily chlorofluorocarbons (CFCs), such astrichloro-trifluoromethane (F11), dichlorodifluoromethane (F12) and1,2-dichloro-1,1,2,2-tetrafluoroethane (F114), and occasionally alsoshort-chain alkanes, such as propane, butane and isobutane, were used.

On account of the ozone problem, caused by the elimination offree-radical chlorine atoms from CFCs, in the Montreal Agreement manycountries have come to an understanding that they will no longer useCFCs as propellants in future. Gases, such as carbon dioxide, nitrogenand the like, can admittedly be liquefied under pressure, but are notutilizable as propellants for metered-dose aerosols, because theinternal pressure in the container very greatly decreases withincreasing emptying. However, fluorinated alkanes, in particularhydrofluoroalkanes (in the context of the present invention alsodesignated “HFA”) such as 1,1,1,2-tetrafluoroethane (HFA 134a) and1,1,1,2,3,3,3-heptafluoropropane (HFA 227), have proved suitable CFCsubstitutes for the medicinal area, as they are inert and have a verylow toxicity. On account of their physical properties, such as pressure,density etc., they are particularly suitable for replacing CFCs such asF11, F12 and F114 as propellants in metered-dose aerosols.

However, it has been shown that the customary excipients used inCFC-containing metered-dose aerosols, such as lecithin, sorbitantrioleate and oleic acid, are only inadequately soluble inhydrofluoroalkanes, such as HFA 134 and HFA 227. It has therefore beenproposed either to improve the solubility in a manner known per se byuse of a cosolvent such as ethanol or to coat the active compoundparticles with the surface-active agent or—instead of this—to dispensewith a surface-active agent or to use special, propellant-solublesurface-active agents. These proposals are found, for example, in U.S.Pat. Nos. 2,868,691, 3,014 844, DE-A-2 736 500, EP-A-0 372 777,WO-A-91/11495, EP-A-0 504 112, EP-B-0 550 031, WO-A-91/04011, EP-A-0 504112 and WO-A-92/00 061.

It is generally known that in the case of suspension formulations onlyactive compound particles which are smaller than 6 μm are respirable.For the desired deposition of the active compounds in the lungs, thesemust therefore be comminuted or micronized by means of specificprocesses, such as pinned-disk, ball or air-jet mills. A grindingprocess, however, as a rule leads to an increase in surface area, whichis accompanied by an increase in the electrostatic charge of themicronized active compound, whereby the flow behaviour and the activecompound dispersion is then usually impaired. As a result of theinterfacial and charge activities, there is frequently an agglomerationof active compound particles or alternatively adsorption of activecompound at interfaces, which becomes conspicuous, for example, in theaccumulation on equipment or container surfaces.

In aerosol preparations in which the active compound is presentsuspended in liquefied propellant, deposition or ring formation canoccur in the container at the position where the liquid phase changesinto the gas phase. Without wetting the micronized active compoundparticles or conducting away charges and modifying their surfaceproperties, suspensions can only be inadequately stabilized or kept in adispersed state. The lack of wetting or dispersion of the activecompound particles also has the result that these in many cases have ahigh tendency for adsorption and stick to surfaces, such as thecontainer inner wall or the valve, which then leads to an underdosageand to a poor dosage accuracy from puff of spray to puff of spray. Inthe case of suspensions, it is therefore as a rule necessary to add asurface-active excipient or a lubricant in order to lower the adsorptionon interfaces and to achieve an acceptable dosage accuracy. A change orreduction in the proportion of the inhalable, respirable particles, theso-called fine particle dose (FPD), occurring in the course of storage,which leads to a decrease in the activity of the aerosol formulation, isparticularly problematical.

To overcome these problems, as a rule permitted surface-activesubstances are added, as have already been used earlier in theCFC-containing formulations. Alternatively to this, in certain cases amodification of the surface properties by means of various measures(e.g. coating) can help to minimize these undesired effects. Because,however, surface-active agents such as oleic acid, sorbitan trioleateand lecithin only dissolve inadequately in hydrofluoroalkanes such asHFA 134a and/or HFA 227, a polar cosolvent such as ethanol is or must beadded so that the pharmaceutical technology problems can be controlledbetter.

If, however, ethanol is added in a higher concentration, the density ofthe propellant mixture decreases, which can lead to an undesireddemixing, especially in the case of suspensions. Moreover, a “wet spray”can undesirably be obtained, because the propellant evaporates much morerapidly than ethanol. In addition, however, as a result of the increasein the solubility during storage, dissolving effects can occur whichthen lead to crystal growth and in turn to a reduction in the amount ofinhalable, respirable particles, the so-called fine particle dose (FPD).

It is additionally disadvantageous that in the case of ethanolconcentrations of, for example, 10% or more, the proportion of inhalableparticles (<6 μm) decreases, because the spray can produce particleshaving a greater aerodynamic diameter on account of the differentevaporation properties of ethanol and the propellant. As a result ofthis, there is a reduction in the fine particle dose (FPD) crucial forthe activity. This may explain why most commercially availablemetered-dose aerosols have been formulated as suspensions.

In the case of ethanol-containing aerosols, there are moreover alsooccasionally problems of active compound stability in the case ofsuspension formulations. In addition, the active compound stability, theactive compound dispersion and the fine particle dose can also beadversely affected by moisture.

To measure the aerodynamic particle size distribution or the FPD or fineparticle fraction (FPF), impactors, such as the 5-stage multistageliquid impinger (MSLI) or 8-stage Andersen cascade impactor (ACI), whichare described in Chapter <601> of the United States Pharmacopeia (USP)or in the inhalants monograph of the European Pharmacopeia (Ph. Eur.)are suitable. By means of the aerodynamic particle distribution, it ispossible by means of a so-called “log-probability plot” (logarithmicrepresentation of the probability distribution) to calculate the meanaerodynamic particle diameter (median mass aerodynamic diameter (MMAD))of aerosol preparations. Using this information on particledistribution, information is obtained as to whether the active compoundis more easily deposited in the upper or lower area of the lungs.

As follows from the preceding text, adherence to a high dosage accuracy,i.e. the constant release of active compound from puff of spray to puffof spray, is a fundamental problem of suspension metered-dose aerosols,which is made additionally difficult by the replacement of CFCs. Inaddition to the valve and actuator, the dosage accuracy essentiallydepends on the suspension properties, i.e. on how easily andhomogeneously the active compound is dispersed in the propellant and howlong the suspension remains in this labile equilibrium state withoutchange in its physical properties. The maintenance of a high dosageaccuracy in the case of potent, low-dose active compounds provesparticularly difficult. For example, for the long-acting beta-agonistformoterol fumarate, which is already therapeutically active in very lowdoses (6 μg/stroke), a formulation is needed which affords an adequatelystable suspension which does not adhere to interfaces and does notchange in the course of storage under different temperature and moistureconditions. A general survey of the products found on the market showsthat to date there is no metered-dose aerosol which can meter activecompounds in amounts of less than 10 μg per stroke (i.e. per puff ofspray) with a mean variation of better than ±25%.

SUMMARY OF THE INVENTION

The invention is therefore based on the object of avoiding the mentionedproblems of suspension metered-dose aerosols to the greatest possibleextent, and in particular of making available a medicinal suspensionaerosol formulation which has improved suspension and shelf-lifeproperties, suppresses to the greatest possible extent thedisadvantageous effect of water on the stability and dispersion ofactive compounds and permits a high dosage accuracy—even in the case oflow-dose active compounds.

The object is achieved according to the invention by a medicinal aerosolformulation, comprising a solid, pharmaceutically acceptable salt ofcromoglycic acid and/or nedocromil in a therapeutically andprophylactically inefficacious amount, an efficacious amount of a finelydivided pharmaceutically active compound which is different therefrom,having a mean particle diameter of less than 6 μm, and a non-toxicliquid propellant, in which the active compound is present in suspendedform.

DETAILED DESCRIPTION OF THE INVENTION

It has in fact surprisingly been found that the addition of cromoglycicacid and/or nedocromil salts in subtherapeutic concentrations of, forexample, 5-100 μg/stroke is very helpful in suspending pharmaceuticallyactive compounds in hydrofluoroalkanes and other propellants. Thesesubstances, so-called mast cell inhibitors, have been employed until nowin the form of their sodium salts in topical preparations (eye drops,nasal sprays) and as antiallergics in inhalation products. For example,FR-A-2 339 604 discloses disodium cromoglycate having a water content ofless than 5% by weight and aerosol formulations having a water contentof less than 1% by weight which contain 1-20% by weight of finelydivided disodium cromoglycate and, as a propellant, preferably CFCs suchas F11, F12 and F114. In WO-A-91/11495, propellant mixtures whichcontain a partly fluorinated lower alkane such as HFA 227, HFA 125, HFA134a or HFA 152a, and powder aerosols based on such propellant mixturesare described, suitable pharmaceuticals, inter alia antiallergics suchas disodium cromoglycate and nedocromil and furthermore also activecompound combinations of disodium cromoglycate with betamimetics or PAFantagonists being mentioned as examples. In WO-A-92/00061, aerosolformulations comprising a fluorocarbon propellant, a polyethoxylatedsurface-active agent and a medicament are disclosed, where themedicament used can preferably be the salt of a dicarboxylic acid, forexample a salt of nedocromil or cromoglycic acid. In the previouslyknown formulations, the cromoglycic acid or nedocromil salts, however,are in each case employed in inhalable form and in a therapeuticallyand/or prophylactically active concentration.

In commercial applications, disodium cromoglycate is employed inmetered-dose aerosols in concentrations of 1 mg and 5 mg/stroke and ininhalation solutions and powders in concentrations of 20 mg perapplication. Such products are obtainable under the trade name Intal®(Fisons) and are also supplied as generics by various firms. Nedocromilsodium is therapeutically employed as Tilade® metered-dose aerosol(Fisons) in a concentration of 2 mg/stroke. In addition, there are alsocombination products of the antiallergic disodium cromoglycate and abeta-agonist, which contain 1 mg of disodium cromoglycate and, forexample, 0.5 mg of reproterol hydrochloride (Aarane® from Fisons,Allergospasmin® from Asta Medica) or 0.05 mg of fenoterol hydrobromide(Ditec® from Thomae) per puff of spray.

Surprisingly, it has further been found that instead of known carrierspermitted for inhalation, such as lactose or glucose, the high-doseactive compounds cromoglycic acid and nedocromil can be used as carriersif these are employed in subtherapeutic doses in the form of theirsalts. Pharmaceutically acceptable salts of both substances are suitablefor protecting other active compounds and for obtaining metered-doseaerosols having advantageous product properties. If a pharmaceuticallyactive compound such as formoterol fumarate is mixed with apharmaceutically acceptable salt of cromoglycic acid and/or nedocromilas a carrier, a powder mixture is obtained which can usually also bereadily suspended in the customary propellants without a surface-activeagent. The anionic carrier materials according to the invention, whichcan be present, for example, in the form of their sodium salts, formassociations, on account of their chemical charges, with activecompounds, such as formoterol fumarate, levalbuterol sulfate and thelike, which can also be accurately metered in very low dosages.

Surprisingly, it has additionally been found that salts of cromoglycicacid and nedocromil, such as disodium cromoglycate and nedocromilsodium, improve the chemical and physical stability ofmoisture-sensitive active compounds, such as levalbuterol sulfate,formoterol fumarate and the like, which possibly could be attributed totheir hygroscopicity, in that they keep away the negative influence ofthe water on moisture-sensitive active compounds to a certain extent.

The tendency to adhesion, of electrostatically charged active compoundssuch as micronized corticosteroids is moreover reduced by admixture ofsalts of cromoglycic acid and/or nedocromil, such as disodiumcromoglycate and/or nedocromil sodium, and their dispersion propertiesare improved.

The use according to the invention of pharmaceutically acceptable saltsof cromoglycic acid and/or nedocromil as carrier materials intherapeutically and prophylactically inefficacious amounts thereforepermits the preparation of improved suspension aerosol formulations, itbeing possible, if desired, to dispense completely or largely withexcipients such as oleic acid, sorbitan trioleate, lecithin, lactose andglucose, which dissolve only inadequately or not at all inhydrofluoroalkanes such as HFA 134a and HFA 227. A further advantage ofthe carrier materials used according to the inventions is that thesodium salts are already permitted as active compounds in a relativelyhigh dose and thus expensive safety tests for the demonstration of theirharmlessness are unnecessary.

The aerosol formulation according to the invention is fundamentallysuitable for any desired pharmaceutically active compounds which can beadministered as suspension aerosols in therapeutically orprophylactically efficacious amounts in each case. Examples of preferredactive compounds are beta-mimetics, anticholinergics, antiallergics andanti-inflammatory active compounds (e.g. corticosteroids, leukotrieneantagonists, cytokinin inhibitors, calcium channel openers etc.).Formulations are particularly preferred which as pharmaceutically activecompound contain formoterol, salmeterol, fenoterol, clenbuterol,levalbuterol, ipratropium, oxitropium, glycopyrronium, tiotropium,budesonide, ciclesonide, mometasone, fluticasone, beclomethasone,flunisolide, loteprednol, triamcinolone, amiloride, rofleponide or apharmaceutically acceptable salt or derivative of these activecompounds, such as formoterol fumarate, formoterol tartrate, salmeterolxinafoate, fenoterol hydrobromide, clenbuterol hydrochloride,ipratropium bromide, oxitropium bromide, glycopyrronium bromide,tiotropium bromide, mometasone furoate, fluticasone dipropionate,beclomethasone dipropionate or flunisolide acetate, where opticallyactive active compounds can be used in the form of their active isomeror as an isomer mixture (e.g. racemate). If desired, the aerosolformulations according to the invention can also contain two or morepharmaceutically active compounds, combinations of fluticasone,ipratropium, oxitropium, glycopyrronium, tiotropium, budesonide,mometasone, ciclesonide, rofleponide or a pharmaceutically acceptablesalt or derivative thereof with levalbuterol, formoterol and/orsalmeterol or a pharmaceutically acceptable derivative thereof beingpreferred. If desired, the aerosol formulations according to theinvention can also contain dissolved active compounds; it is onlyessential to the invention that at least one pharmaceutically activecompound is present in suspended form. As follows from the explanationsbelow, however, pharmaceutically acceptable cromoglycic acid andnedocromil salts according to the invention are only used as carriers,i.e. the “pharmaceutically active compound” in the context of thepresent invention is not a pharmaceutically acceptable salt ofcromoglycic acid or nedocromil.

The aerosol formulation according to the invention is particularlyadvantageous for the administration of low-dose active compounds. Theinvention therefore in particular also relates to aerosol formulationsof active compounds which can be administered in an efficacious dose ofapproximately 0.1 to 100 μg per puff of spray, those with a dose of atmost approximately 50 μg being preferred and those with a dose ofapproximately 0.1 to 20 μg being particularly preferred. The strokemasses of commercially available MDIs (metered-dose inhalers) areusually in the range from approximately 30 to 130 mg (with valvescorrespondingly from approximately 25 to 100 μl) and are typicallyapproximately 70 mg per puff of spray. Accordingly, the preferredaerosol formulations of low-dose active compounds as a rule containapproximately 0.0001 to 0.2% by weight, in particular at mostapproximately 0.1% by weight and particularly preferably approximately0.0001 to 0.04% by weight, of suspended active compound.

The active compound to be suspended or the active compounds to besuspended can be micronized in a manner known per se, e.g. by means ofpinned-disk, ball or air-jet mills or obtained by controlledmicrocrystallization or precipitation and suspended in the propellant.Expediently, the mean particle diameter of the active compound particlesshould be at least 6 μm and preferably at least approximately 1 μm, the“mean particle diameter” in the context of the present inventiondesignating the mean (mass mean) aerodynamic particle diameter known asthe median mass aerodynamic diameter (MMAD).

The salts of cromoglycic acid or nedocromil used as carriers canpreferably likewise be present in the aerosol formulations according tothe invention in suspended form having an mean particle diameter of lessthan 6 μm (preferably at least approximately 1 μm) They can bemicronized to the desired particle size in a manner known per se, eitheron their own or together with the pharmaceutically active compound orthe pharmaceutically active compounds, and suspended in the propellant.If desired, the cromoglycic acid and nedocromil salts, however, can alsobe used in a relatively large particle size if it is desired that thesesalts are not sprayed or do not pass into the lungs.

Suitable carriers are in principle all pharmaceutically acceptable saltsof cromoglycic acid or of nedocromil in which one or both carboxylgroups are present in deprotonated, i.e. anionic, form. The alkali metalsalts and the alkaline earth metal salts can preferably be used, inparticular the sodium and potassium salts, disodium cromoglycate andnedocromil sodium being particularly preferred.

Disodium cromoglycate and nedocromil sodium are used—as mentionedabove—in known metered-dose aerosols in a therapeutically orprophylatically efficacious amount of customarily 1 mg or 2 mg per puffof spray. In contrast, the pharmaceutically acceptable salts ofcromoglycic acid and of nedocromil are not used according to theinvention as therapeutic or prophylactic active compounds, but merely ascarriers and accordingly only in amounts which have no significanttherapeutic or prophylactic action. The amounts of cromoglycic acidsalts or nedocromil salts used according to the invention are thereforeas a rule not over 500 μg per puff of spray, where in general amounts ofapproximately 5 to 250 μg, in particular approximately 10 to 100 μg, perpuff of spray are preferred. The proportion of cromoglycic acid salts ornedocromil salts in the aerosol formulations according to the inventionis therefore as a rule not over approximately 0.7% by weight and ispreferably approximately 0.007 to 0.36% by weight, in particularapproximately 0.015 to 0.15% by weight, based on the total formulation.

Based on the suspended active compound, the proportion of cromoglycicacid and nedocromil salts can vary within a relatively wide range. Ingeneral, however, the weight ratio of the cromoglycic acid salts and/ornedocromil salts to the suspended pharmaceutically active compound or tothe suspended pharmaceutically active compounds is approximately 10:1 toapproximately 1:10, preferably approximately 5:1 to approximately 1:5.

Preferably, the cromoglycic acid and/or nedocromil salt can be selectedin comparison to the pharmaceutically active compound such that thedensity of these materials is comparable overall with the density of thepropellant. For example, micronized formoterol fumarate, which tends tofloat in HFA 227, can be combined with disodium cromoglycate, whichtends to sediment, in order to keep the suspended material better insuspension and to minimize flotation or sedimentation.

Suitable non-toxic liquid propellants for the aerosol formulationsaccording to the invention are in principle all pressure-liquefiedpropellants which can be used customarily in metered-dose aerosols, forexample fluorochlorocarbons such as trichloro-monofluoromethane (F11),dichlorodifluoromethane (F12), monochlorotrifluoromethane (F13),dichloro-monofluoromethane (F21), monochlorodifluoromethane (F22),monochloromonofluoromethane (F31), 1,1,2-trichloro-1,2,2-trifluoroethane(F113), 1,2-dichloro-1,1,2,2-tetrafluoroethane (F114),1-chloro-1,1,2,2,2-pentafluoroethane (F115),2,2-dichloro-1,1,1-trifluoroethane (F123),1,2-dichloro-1,1,2-trifluoroethane (F123a),2-chloro-1,1,1,2-tetrafluoroethane (F124),2-chloro-1,1,2,2-tetrafluoroethane (F124a),1,2-dichloro-1,1-difluoroethane (F132b), 1-chloro-1,2,2-trifluoroethane(F133), 2-chloro-1,1,1-trifluoroethane (F133a),1,1-dichloro-1-fluoroethane (F141b) and 1-chloro-1,1-difluoroethane(F142b), alkanes such as propane, butane and isobutane, fluorinatedalkanes such as octafluoropropane (F218) and in particularhydrofluoroalkanes such as difluoromethane (HFA 32), pentafluoroethane(HFA 125), 1,1,2,2-tetrafluoroethane (HFA 134),1,1,1,2-tetrafluoroethane (HFA 134a), 1,1,2-trifluoroethane (HFA 143),1,1,1-trifluoroethane (HFA 143a), difluoroethane (HFA 152a),1,1,1,2,3,3,3-heptafluoropropane (HFA 227) and the like.

Preferred propellants are the hydrofluoroalkanes of the general formula.

C_(x)H_(y)F_(z)  (I)

in which x is the number 1, 2 or 3, y and z are each an integer ≧1 andy+z=2x+2.

As a rule, those hydrofluoroalkanes of the formula I in which x is thenumber 2 or 3 are particularly suitable.

Particularly preferred aerosol formulations are those which contain HFA134 or HFA 227 or mixtures of these two propellants. HFA 134a and HFA227 have a vapor pressure of about 6 bar and about 4.2 bar respectivelyat 20° C. Both propellants differ with respect to their density (about1.2 g/ml for HFA 134a and about 1.4 g/ml for HFA 227), which isimportant insofar as it is possible by suitable choice of the propellantor propellant mixture to match its density better to the density of thesuspended substances and thus to keep the latter better in suspension.If desired, the density of the propellant can be further reduced byaddition of cosolvents or other propellants, such as ethanol, diethylether, propane, n-butane or isobutane.

The aerosol formulations according to the invention can preferablycontain one or more hydrofluoroalkanes of the formula I, particularlypreferably 1,1,1,2-tetrafluoroethane (HFA 134a) and/or1,1,1,2,3,3,3-heptafluoropropane (HFA 227), and their proportion in thetotal formulation can preferably be at least approximately 50% by weightand particularly preferably at least approximately 80% by weight. As arule, it is advantageous to employ these propellants in an amount of 90%by weight or more.

If desired, the aerosol formulations according to the invention cancontain nitrogen or in particular dinitrogen monoxide (laughing gas)and/or carbon dioxide in an amount of approximately 0.0001 to 10% byweight as a further propellant. Concentrations of approximately 0.01 to3% by weight are in general preferred and concentrations ofapproximately 0.1 to 1.0% by weight are particularly preferred; higherconcentrations are as a rule only useful if the formulation contains acomparatively high proportion of cosolvents. It has in fact surprisinglybeen found that propellants with more advantageous properties can beobtained if a small amount of dinitrogen monoxide and/or carbon dioxideis added to the customary propellants, in particular to thehydrofluoroalkanes mentioned. Propellant mixtures of this type—incontrast to dinitrogen monoxide and carbon dioxide as the solepropellants—show only a slight decrease in the internal pressure in thecontainer as it becomes more empty, which makes possible their use aspropellants for metered-dose aerosols. Moreover, it has surprisinglybeen found that the addition of dinitrogen monoxide and/or carbondioxide facilitates the suspension of pharmaceutical active compounds,whereby the addition of surface-active substances and/or cosolvents canbe more easily dispensed with or at least the proportion thereof can bereduced. In addition, it has been found that by addition of dinitrogenmonoxide and/or carbon dioxide, the undesired deposition of activecompound in the oropharynx can be reduced and at the same time the fineparticle dose can be increased. Furthermore, by addition of thesepropellants oxygen can be displaced from the hydrofluoroalkanes or otherpropellants, which improves the storage stability of oxidation-sensitiveactive compounds, and, depending on the amount of dinitrogen monoxideand/or carbon dioxide, the internal pressure in the aerosol containercan be adjusted in such a way as is most useful for the particularapplication.

In general, aerosol formulations are preferred which have a pressure ofapproximately 3 to 10 bar, in particular approximately 3.5 to 6 bar, at20° C. When using cosolvents or propellants having a low vapor pressure,a pressure which is in any case lower can preferably be correspondinglyincreased by addition of dinitrogen monoxide and/or carbon dioxide.

The aerosol formulations according to the invention can be prepared in amanner known per se by adding the propellant to the micronizedpharmaceutically active compound and a pharmaceutically acceptable saltof cromoglycic acid and/or nedocromil and, if desired, introducingdinitrogen monoxide and/or carbon dioxide under pressure. These stepscan in principle be carried out in any desired sequence. When usingdinitrogen monoxide and/or carbon monoxide, however, as a rule it ispreferred firstly to introduce this/these into the propellant and thento add the micronized active compound and the cromoglycic acid and/ornedocromil salt. The formulations can be prepared using customarystirrers and homogenizers. For dispensing, known processes, such as thecold- or pressure-filling technique or modifications of thesetechniques, can be employed. Suitable containers are, for example,pressure-resistant containers made of glass, plastic or aluminum, whichcan be equipped with metered-dose valves of, for example, 10 to 140 μland can be provided with commercially available—alsoinspiration-triggered—mouth tube adapters.

Although the addition of cosolvents and surface-active agents is usuallyunnecessary as a result of the use of cromoglycic acid and/or nedocromilsalts and in any case as a result of the use of dinitrogen monoxideand/or carbon dioxide, the addition of a small amount of cosolvent canoccasionally be advantageous. Suitable cosolvents are, for example,water, alcohols having 1 to 3 carbon atoms, alkanes having 3 to 6 carbonatoms and dialkyl ethers having 2 to 4 carbon atoms. Examples ofpreferred cosolvents are: ethanol, propanol, isopropanol, ethyleneglycol, propylene glycol, glycerol, propane, butane, isobutane, pentane,dimethyl ether and diethyl ether, with ethanol, glycerol, propyleneglycol and diethyl ether or mixtures thereof and in particular ethanolas a rule being particularly preferred. Preferred cosolvent mixturesusing which a glidant action is simultaneously achieved are ethanoltogether with glycerol and/or propylene glycol and also diethyl ethertogether with glycerol and/or propylene glycol. In general, theproportion of cosolvents, if present, is not over approximately 15% byweight, preferably not over approximately 10% by weight and usually notover approximately 5% by weight, based on the total formulation.

The aerosol formulations according to the invention can preferably beessentially free of surface-active agents, i.e. preferably contain lessthan approximately 0.0001% by weight of surface-active agents. Ifdesired, however, they can contain surface-active agents such as oleicacid, lecithin, sorbitan trioleate, cetylpyridinium chloride,benzalkonium chloride, polyoxyethylene (20) sorbitan monolaurate,polyoxyethylene (20) sorbitan monostearate, polyoxyethylene (20)sorbitan monooleate, polyoxypropylene/polyoxyethylene block copolymers,polyoxypropylene/polyoxyethylene/ethylenediamine block copolymers,ethoxylated castor oil and the like, where the proportion ofsurface-active agents, if present, can preferably be approximately0.0001 to 1% by weight, in particular approximately 0.001 to 0.1% byweight, based on the total formulation.

Furthermore, if desired, the aerosol formulations according to theinvention can contain buffer substances or stabilizers such as citricacid, ascorbic acid, sodium EDTA, vitamin E, N-acetylcysteine and thelike. In general, such substances, if present, are used in amounts ofnot more than approximately 1% by weight, for example in an amount offrom approximately 0.0001 to 1% by weight, based on the totalformulation.

The use according to the invention of cromoglycic acid and/or nedocromilsalts thus permits the preparation of improved suspension aerosolformulations of pharmaceutically active compounds, in particular oflow-dose active compounds. The invention therefore likewise relates tothe use of a solid, pharmaceutically acceptable salt of cromoglycic acidand/or nedocromil in a therapeutically and prophylacticallyinefficacious amount in a medicinal suspension aerosol formulation forreducing undesired adsorption or for improving the dosage accuracyand/or reducing the moisture sensitivity of a suspended pharmaceuticalactive compound.

Using the formulation technology according to the invention, it is thuspossible to prepare active compounds or active compound combinations asmetered-dose aerosols having more advantageous properties, as is furtherillustrated below by means of some examples.

EXAMPLE 1

6 g of micronized formoterol fumarate and 12 g of micronized disodiumcromoglycate are weighed into a pressure addition vessel. After closingand evacuating the addition vessel, 35 g each of HFA 134a and HFA 227,which have previously been treated with 3% by weight of ethanol inanother pressure addition vessel, are added with stirring. Afterhomogenization, the suspension obtained is dispensed by means of thepressure-filling technique into aluminum containers sealed withmetered-dose valves.

EXAMPLE 2

2 g of micronized ipratropium bromide and 10 g of micronized disodiumcromoglycate are mixed and weighed into a pressure addition vessel.After closing and evacuating the addition vessel, 10 kg of HFA 227,which have previously been aerated with carbon dioxide in anotherpressure addition vessel and adjusted to a pressure of 5 bar at 20°C.,are added. After homogenizing this mixture, the suspension obtained isdispensed by means of the pressure-filling technique into aluminumcontainers sealed with metered-dose valves.

EXAMPLE 3

2.5 g of micronized glycopyrronium bromide and 2.5 g of micronizednedocromil sodium are mixed and weighed into a pressure addition vessel.After closing and evacuating the addition vessel, 10.5 kg of apropellant mixture of HFA 227 and HFA 134a (weight ratio 90:10), whichhave previously been treated with 1% by weight of ethanol in anotherpressure addition vessel and aerated with dinitrogen oxide and adjustedto a pressure of 5.5 bar at 20° C., are added. After homogenizing thismixture, the suspension obtained is dispensed by means of thepressure-filling technique into aluminum containers sealed withmetered-dose valves.

EXAMPLE 4

A powder mixture, consisting of 5 g of micronized formoterol fumarate,20 g of micronized glycopyrronium bromide and 25 g of micronizeddisodium cromoglycate, is weighed into a pressure addition vessel. Afterclosing and evacuating the addition vessel, 70 g of HFA 227, which havepreviously been treated with 2% by weight of ethanol in another pressureaddition vessel and aerated with dinitrogen oxide and adjusted to apressure of 5 bar at 20° C., are added with stirring. Afterhomogenization, the suspension obtained is dispensed by means of thepressure-filling technique into aluminum containers sealed withmetered-dose valves.

EXAMPLE 5

2.5 g of micronized glycopryrronium bromide, 5 g of micronizedlevalbuterol and 5 g of micronized nedocromil sodium are weighed into apressure addition vessel. After closing and evacuating the additionvessel, 10.5 kg of a propellant mixture of HFA 227 and HFA 134a (weightratio 80:20), which have previously been aerated in another pressureaddition vessel with dinitrogen oxide and adjusted to a pressure of 5.25bar at 20° C., are added. After homogenizing this mixture, thesuspension obtained is dispensed by means of the pressure-fillingtechnique into aluminum containers sealed with metered-dose valves.

EXAMPLE 6

5 g of micronized formoterol fumarate, 30 g of micronized fluticasonepropionate and 10 g of micronized disodium cromoglycate are weighed intoa pressure addition vessel. After closing and evacuating the additionvessel, 70 kg of HFA 227, which have previously been treated with 2% byweight of ethanol in another pressure addition vessel and aerated withdinitrogen oxide and adjusted to a pressure of 5 bar at 20° C., areadded with stirring. After homogenization, the suspension obtained isdispensed by means of the pressure-filling technique into aluminumcontainers sealed with metered-dose valves.

EXAMPLE 7

20 g of micronized tiotropium bromide and 10 g of micronized nedocromilsodium are weighed into a pressure addition vessel. After closing andevacuating the addition vessel, 70 kg of a propellant mixture of HFA 227and HFA 134a (weight ratio 70:30), which have previously been treatedwith 0.5% by weight of ethanol in another pressure addition vessel, areadded with stirring. After homogenization, the suspension obtained isdispensed by means of the pressure-filling technique into aluminumcontainers sealed with metered-dose valves.

EXAMPLE 8

3 g of micronized glycopyrronium bromide, 3 g of micronized salmeterolxinafoate and 3 g of micronized disodium cromoglycate are mixed andweighed into a pressure addition vessel. After closing and evacuatingthe addition vessel, 10.5 kg of a propellant mixture of HFA 227 and HFA134a (weight ratio 75:25), which have previously been aerated withdinitrogen oxide in another pressure addition vessel and adjusted to apressure of 5.25 bar, are added. After homogenizing this mixture, thesuspension obtained is dispensed by means of the pressure-fillingtechnique into aluminum containers sealed with metered-dose valves.

EXAMPLE 9

A powder mixture, consisting of 10 g of micronized budesonide and 1 g ofmicronized disodium cromoglycate, is weighed into a pressure additionvessel. After closing and evacuating the addition vessel, 7 kg of apropellant mixture of HFA 227 and HFA 134a (weight ratio 65:35), whichhave previously been treated with 1% by weight of ethanol in anotherpressure addition vessel, are added with stirring. After homogenization,the suspension obtained is dispensed by means of the pressure-fillingtechnique into aluminum containers sealed with metered-dose valves.

EXAMPLE 10

0.5 g of micronized formoterol fumarate and 2.0 g of micronized disodiumcromoglycate are weighed into a pressure addition vessel. After closingand evacuating the addition vessel, 7.0 kg of HFA 227, which havepreviously been treated with 3% by weight of ethanol and 0.02% by weightof glycerol and aerated with dinitrogen oxide and adjusted to a pressureof 5 bar at 20° C. in another pressure addition vessel, are added withstirring. After homogenization, the suspension obtained is dispensed bymeans of the pressure-filling technique into aluminum containers sealedwith metered-dose valves.

EXAMPLE 11

A powder mixture, consisting of 10 g of micronized budesonide, 0.5 g ofmicronized formoterol tartrate and 1 g of disodium cromoglycate, isweighed into a pressure addition vessel. After closing and evacuatingthe addition vessel, 70 kg of HFA 227, which have previously beentreated in another pressure addition vessel with 2% by weight of ethanoland 0.2% by weight of propylene glycol, are added with stirring. Afterhomogenization, the suspension obtained is dispensed by means of thepressure-filling technique into aluminum containers sealed withmetered-dose valves.

EXAMPLE 12

A powder mixture, consisting of 0.5 g of micronized formoterol tartrate,10 g of micronized fluticasone dipropionate and 1 g of micronizeddisodium cromoglycate, is weighed into a pressure addition vessel. Afterclosing and evacuating the addition vessel, 7 kg of HFA 227, which havepreviously been treated with 2% by weight of diethyl ether and 0.02% byweight each of benzalkonium chloride, citric acid and propylene glycolin another pressure addition vessel, are added with stirring. Afterhomogenization, the suspension obtained is dispensed by means of thepressure-filling technique into aluminum containers sealed withmetered-dose valves.

EXAMPLE 13

3 g of micronized glycopyrronium bromide, 3 g of micronized salmeterolxinafoate, 3 g of micronized disodium cromoglycate, 0.03 g of sodiumEDTA and 0.03 g of glycerol are mixed and weighed into a pressureaddition vessel. After sealing and evacuating the addition vessel, 10.5kg of a propellant mixture of HFA 227 and HFA 134a (weight ratio 75:25),which have previously been aerated with dinitrogen oxide and adjusted toa pressure of 5.25 bar in another pressure addition vessel, are added.After homogenizing this mixture, the suspension obtained is dispensed bymeans of the pressure-filling technique into aluminum containers sealedwith metered-dose valves.

What is claimed is:
 1. A medicinal aerosol formulation, comprising asolid, pharmaceutically acceptable salt of at least one compoundselected from the group consisting of cromoglycic acid and nedocromil,in a therapeutically and prophylactically inefficacious amount in therange from 5 to 250 μg per puff of spray, an efficacious amount of afinely divided pharmaceutically active compound which is different fromsaid salt, having a mean particle diameter of less than 6 μm, and anon-toxic liquid propellant, in which said active compound is present insuspended form.
 2. The aerosol formulation as claimed in claim 1,wherein said salt is selected from the group consisting of alkali metalsalts and alkaline earth metal salts.
 3. The aerosol formulation asclaimed in claim 1, wherein said salt is selected from the groupconsisting of disodium cromoglycate and nedocromil sodium.
 4. Theaerosol formulation as claimed in claim 1, wherein said salt is presentin suspended form having a particle size of less than 6 μm.
 5. Theaerosol formulation as claimed in claim 1, wherein said salt is presentin an amount of from 10 to 100 μg, per puff of spray.
 6. The aerosolformulation as claimed in claim 1, wherein said salt and said suspendedpharmaceutically active compound are present in a weight ratio of saidsalt to the suspended pharmaceutically active compound of from 10:1 to1:10.
 7. The aerosol formulation as claimed in claim 1, wherein saidpharmaceutically active compound is selected from the group consistingof beta-mimetics, anticholinergics, antiallergics and antiinflammatoryactive compounds.
 8. The aerosol formulation as claimed in claim 1,wherein said pharmaceutically active compound is selected from the groupconsisting of formoterol, salmeterol, fenoterol, clenbuterol,levalbuterol, ipratropium, oxitropium, glycopyrronium, tiotropium,budesonide, ciclesonide, mometasone, fluticasone, beclomethasone,flunisolide, loteprednol, triamcinolone, amiloride, rofleponide andpharmaceutically acceptable salts and derivatives thereof.
 9. Theaerosol formulation as claimed in claim 1, wherein the suspended activecompound is present in an amount of from 0.0001% to 0.2% by weight,based on the total weight of the formulation.
 10. The aerosolformulation as claimed in claim 1, wherein said pharmaceutically activecompound comprises at least one compound selected from the groupconsisting of fluticasone, ipratropium, oxitropium, glycopyrronium,tiotropium, budesonide, mometasone, ciclesonide, rofleponide andpharmaceutically acceptable salts and derivatives thereof, and theaerosol formulation further comprising an active compound selected fromthe group consisting of levalbuterol, formoterol, salmeterol andpharmaceutically acceptable derivatives thereof.
 11. The aerosolformulation as claimed in claim 1, wherein the propellant comprises oneor more hydrofluoroalkanes of formula C_(x)H_(y)F_(z)  (I) in which x is1, 2 or 3, y and z are each an integer ≧1 and y+z=2x+2.
 12. The aerosolformulation as claimed in claim 1, wherein said propellant comprises atleast one compound selected from the group consisting of1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3,3-heptafluoropropane.
 13. Theaerosol formulation as claimed in claim 1, further comprising at leastone compound selected from the group consisting of dinitrogen monoxideand carbon dioxide in an amount of from 0.0001% to 10% by weight, basedon the total weight of the formulation.
 14. The aerosol formulation asclaimed in claim 1, having a pressure of 3 to 10 bar at 20° C.
 15. Theaerosol formulation as claimed in claim 1, further comprising acosolvent.
 16. The aerosol formulation as claimed in claim 15,comprising at most 15% by weight of said cosolvent, based on the totalweight of the formulation.
 17. The aerosol formulation as claimed inclaim 1, being essentially free of surface-active agents.
 18. Theaerosol formulation as claimed in claim 1, wherein said salt is selectedfrom the group consisting of sodium salts and potassium salts.
 19. Theaerosol formulation as claimed in claim 1, wherein said salt and saidsuspended pharmaceutically active compound are present in a weight ratioof said salt to said suspended pharmaceutically active compound of from5:1 to 1:5.
 20. The aerosol formulation as claimed in claim 1, whereinsaid suspended pharmaceutically active compound is present in an amountof from 0.0001% to 0.1% by weight, based on the total weight of theformulation.
 21. The aerosol formulation as claimed in claim 1, furthercomprising at least one compound selected from the group consisting ofdinitrogen monoxide and carbon dioxide in an amount of from 0.01% to 3%by weight, based on the total weight of the formulation.
 22. The aerosolformulation as claimed in claim 1, having a pressure of 3.5 to 6 bar at20° C.
 23. The aerosol formulation as claimed in claim 15, wherein saidcosolvent is at least one compound selected from the group consisting ofethanol, glycerol, propylene glycol and diethyl ether.
 24. A method ofimproving dosage accuracy of a medicinal suspension aerosol formulationcomprising a finely divided pharmaceutically active compound having amean particle diameter of less than 6 μm, and a non-toxic liquidpropellant, in which the active compound is present in suspended form,said method comprising adding to said formulation a solid,pharmaceutically acceptable salt of at least one compound selected fromthe group consisting of cromoglycic acid and nedocromil, in atherapeutically and prophylactically inefficacious amount.
 25. A methodof reducing moisture sensitivity of a suspended pharmaceutically activecompound in a medicinal suspension aerosol formulation comprising saidpharmaceutically active compound in finely divided form having a meanparticle diameter of less than 6 μm, and a non-toxic liquid propellant,in which said active compound is present in suspended form, said methodcomprising adding to said formulation a solid, pharmaceuticallyacceptable salt of at least one compound selected from the groupconsisting of cromoglycic acid and nedocromil, in a therapeutically andprophylactically inefficacious amount.